US8394820B2 - N-azabicyclic carboxamide derivatives, preparation thereof and therapeutic use thereof - Google Patents

N-azabicyclic carboxamide derivatives, preparation thereof and therapeutic use thereof Download PDF

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US8394820B2
US8394820B2 US12/840,664 US84066410A US8394820B2 US 8394820 B2 US8394820 B2 US 8394820B2 US 84066410 A US84066410 A US 84066410A US 8394820 B2 US8394820 B2 US 8394820B2
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cycloalkyl
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alkyl
alkylene
methyl
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Laurent Dubois
Yannick Evanno
André MALANDA
Odile Leclerc
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Sanofi SA
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention satisfies this need by providing azabicyclic carboxamide derivatives that have in vitro and in vivo antagonist or agonist activity on receptors of TRPV1 (or VR1) type.
  • a first subject of the invention concerns the compounds corresponding to the general formula (I) hereinbelow.
  • Another subject of the invention concerns processes for preparing the compounds of general formula (I).
  • Another subject of the invention concerns the use of the compounds of general formula (I) especially in medicaments or in pharmaceutical compositions.
  • X 1 , X 2 , X 3 and X 4 represent, independently of each other, a nitrogen atom or a group C—R 1 ;
  • W represents an oxygen or sulfur atom
  • n is equal to 0, 1, 2 or 3;
  • Y represents an aryl or a heteroaryl optionally substituted with one or more groups chosen from a halogen atom and a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, hydroxyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkylene-O—, C 1 -C 6 -fluoroalkoxy, cyano, C(O) NR 3 R 4 , nitro, NR 3 R 4 , C 1 -C 6 -thioalkyl, thiol, —S(O)—C 1 -C 6 -alkyl, —S(O) 2 -C 1 -C
  • A represents a bicyclic heteroaryl of formula:
  • Z 1 , Z 2 , Z 3 and Z 4 represent, independently of each other, a carbon atom, a nitrogen atom or a group C—R 2a ;
  • Z 5 , Z 6 and Z 7 represent, independently of each other, a nitrogen atom or a group C—R 2b ;
  • Z 8 represents a carbon atom
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 represent a nitrogen atom
  • R 1 is chosen from a hydrogen atom, a halogen atom, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, aryloxy-C 1 -C 6 -alkyl, heteroaryloxy-C 1 -C 6 -alkyl, aryl-C 1 -C 3 -alkylenoxy-C 1 -C 6 -alkyl, heteroaryl-C 1 -C 3 -alkylenoxy-C 1 -C 6 -alkyl, arylthio-C 1 -C 6 -alkyl, heteroarylthio-C 1 -C 6 -alkyl, aryl-C 1 -C 3 -alkylenethio-C 1 -C 6 -alkyl, heteroaryl-C 1 -
  • R 2a represents a hydrogen atom, a halogen atom or a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene-O—, hydroxyl, thiol or C 1 -C 6 -fluoroalkoxy;
  • R 2b represents a hydrogen atom, a halogen atom or a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, hydroxyl, thiol, oxo, thio, C 3 -C 7 -cycloalkyloxy, C 1 -C 6 -fluoroalkoxy, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy, C 1 -C 6 -alkoxy-C 1 -C 3 -alkylene, C 3 -C 7 -cycloalkyloxy-C 1 -C 3 -alkylene, C 3 -C 7 -cycloalkyloxy-C 1 -C 3 -alkylene,
  • R 3 and R 4 represent, independently of each other, a hydrogen atom or a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, aryl-C 1 -C 5 -alkylene or aryl, or R 3 and R 4 together form, with the nitrogen atom that bears them, an azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine or homopiperazine group; the group NR 3 R 4 being optionally substituted with a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, aryl-C 1 -C 6 -alkylene, aryl, heteroaryl, aryl-S(
  • R 5 and R 6 represent, independently of each other, a hydrogen atom or a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, aryl-C 1 -C 6 -alkylene or aryl; the aryl group being optionally substituted with one or more substituents chosen from a halogen atom and a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy, C 1 -C 6 -flu
  • R 5 and R 6 together form a 4- to 7-membered lactam comprising the nitrogen atom and the C(O) group that bear them;
  • R 7 represents a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -akylene, aryl-C 1 -C 6 -alkylene or aryl; the aryl group being optionally substituted with one or more substituents chosen from a halogen atom and a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy, C 1 -C 6 -fluoroalkoxy, nitro or cyano;
  • R 5 and R 7 together form a 4- to 7-membered sultam comprising the nitrogen atom and the S(O) 2 group that bear them;
  • R 8 represents a halogen atom or a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy, C 1 -C 6 -fluoroalkoxy, nitro, cyano, NR 3 R 4 , —C(O)—C 1 -C 6 -alkyl or —C(O)—C 3 -C 7 -cycloalkyl; the groups C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3
  • the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.
  • the compounds of formula (I) may exist in the form of bases or of acid-addition salts. Such addition salts form part of the invention.
  • solvents may be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for purifying or isolating the compounds of formula (I) also form part of the invention.
  • the compounds of formula (I) may also exist in the form of hydrates or solvates, i.e. in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates also form part of the invention.
  • Examples of monocyclic heteroaryls that may be mentioned include imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, furyl, thiophenyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl.
  • bicyclic heteroaryls examples include indolyl, isoindolyl, benzofuryl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothiazolyl, isobenzofuryl, isobenzothiazolyl, pyrrolo[2,3-c]pyridyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3.2-b]pyridyl, pyrrolo[3.2-c]pyridyl, pyrrolo[1,2-a]pyridyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, pyrrolo[1,2-a]imidazolyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridaziny
  • a first subgroup of compounds is constituted by the compounds for which
  • X 1 , X 2 , X 3 and X 4 represent, independently of each other, a group C—R 1 ;
  • R 1 being as defined in the general formula (I).
  • a second subgroup of compounds is constituted by the compounds for which X 1 , X 2 , X 3 and X 4 represent, independently of each other, a nitrogen atom or a group C—R 1 ;
  • R 1 being as defined in the general formula (I).
  • X 1 , X 2 and X 3 represent a group C—R 1 ;
  • X 4 represents a nitrogen atom;
  • R 1 being as defined in the general formula (I).
  • R 1 is chosen from a hydrogen atom, a halogen atom, more particularly a fluorine atom,
  • a fifth subgroup of compounds is constituted by the compounds for which n is equal to 1.
  • a sixth subgroup Y represents an aryl, more particularly a phenyl, optionally substituted with one or more halogen atoms, more particularly fluorine atoms.
  • a seventh subgroup of compounds is constituted by the compounds for which W represents an oxygen atom.
  • an eighth subgroup of compounds is constituted by the compounds for which A represents a bicyclic heteroaryl of formula:
  • Z 1 , Z 2 , Z 3 and Z 4 represent, independently of each other, a carbon atom or a nitrogen atom;
  • Z 5 , Z 6 and Z 7 represent, independently of each other, a nitrogen atom or a group C—R 2b ;
  • Z 8 represents a carbon atom
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 represent a nitrogen atom
  • R 2b being as defined in the general formula (I).
  • A represents a bicyclic heteroaryl of formula:
  • Z 1 , Z 2 , Z 3 and Z 4 represent, independently of each other, a carbon atom or a nitrogen atom;
  • Z 5 , Z 6 and Z 7 represent, independently of each other, a nitrogen atom or a group C—R 2b ;
  • Z 8 represents a carbon atom
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 represent a nitrogen atom
  • R 2b represents a hydrogen atom or a group C 1 -C 6 -alkyl, C(O)O—C 1 -C 6 -alkyl, phenyl or thienyl; the groups C 1 -C 6 -alkyl possibly being substituted with a hydroxyl or C 1 -C 6 -alkoxy group.
  • A represents a bicyclic heteroaryl of formula:
  • Z 1 , Z 2 , Z 3 and Z 4 represent, independently of each other, a carbon atom or a nitrogen atom;
  • Z 5 , Z 6 and Z 7 represent, independently of each other, a nitrogen atom or a group C—R 2b ;
  • Z 8 represents a carbon atom
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 represent a nitrogen atom
  • R 2b represents a hydrogen atom or a methyl, ethyl, tert-butyl, C(O)O-ethyl, phenyl or thienyl group; the methyl groups possibly being substituted with a hydroxyl or methoxy group.
  • an eleventh subgroup of compounds is constituted by the compounds for which
  • A represents the group
  • R 2b being as defined in the general formula (I).
  • A represents the group
  • R 2b represents a hydrogen atom or a group C 1 -C 6 -alkyl, C(O)O—C 1 -C 6 -alkyl, phenyl or thienyl; the groups C 1 -C 6 -alkyl possibly being substituted with a hydroxyl or C 1 -C 6 -alkoxy group.
  • R 2b represents a hydrogen atom or a methyl, ethyl, tert-butyl, C(O)O-ethyl, phenyl or thienyl group; the methyl groups possibly being substituted with a hydroxyl or methoxy group.
  • A represents the group
  • R 2b being as defined in the general formula (I).
  • A represents the group
  • R 2b represents a hydrogen atom or a group C 1 -C 6 -alkyl, phenyl or thienyl; the groups C 1 -C 6 -alkyl possibly being substituted with a hydroxyl or C 1 -C 6 -alkoxy group.
  • A represents the group
  • R 2b represents a hydrogen atom or a methyl, ethyl, tert-butyl, phenyl or thienyl group
  • methyl groups possibly being substituted with a hydroxyl or methoxy group.
  • a seventeenth subgroup of compounds is constituted by the compounds for which the definitions of X 1 , X 2 , X 3 , X 4 , n, Y, W and A given above are combined.
  • an eighteenth subgroup of compounds is constituted by the compounds for which
  • X 1 , X 2 , X 3 and X 4 represent, independently of each other, a group C—R 1 ; or alternatively X 1 , X 2 and X 3 represent a group C—R 1 ; X 4 represents a nitrogen atom;
  • R 1 is chosen from a hydrogen atom, a halogen atom, more particularly a fluorine atom, and a group C 1 -C 6 -fluoroalkyl, more particularly a trifluoromethyl group;
  • n 1;
  • Y represents an aryl, more particularly a phenyl, optionally substituted with one or more halogen atoms, more particularly fluorine atoms;
  • W represents an oxygen atom
  • A represents a bicyclic heteroaryl of formula:
  • Z 1 , Z 2 , Z 3 and Z 4 represent, independently of each other, a carbon atom or a nitrogen atom;
  • Z 5 , Z 6 and Z 7 represent, independently of each other, a nitrogen atom or a group C—R 2b ;
  • Z 8 represents a carbon atom
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 represent a nitrogen atom
  • R 2b represents a hydrogen atom or a group C 1 -C 6 -alkyl, C(O)O—C 1 -C 6 -alkyl, phenyl or thienyl; the groups C 1 -C 6 -alkyl possibly being substituted with a hydroxyl or C 1 -C 6 -alkoxy group.
  • R 2b represents a hydrogen atom, a halogen atom or a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, hydroxyl, thiol, oxo, thio, C 3 -C 7 -cycloalkyloxy, C 1 -C 6 -fluoroalkoxy, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy, C 1 -C 6 -alkoxy-C 1 -C 3 -alkylene, C 3 -C 7 -cycloalkyloxy-C 1 -C 3 -alkylene, C 3 -C 7 -cycloalkyloxy-C 1 -C 3 -alkylene,
  • R 3 and R 4 being as defined in the general formula (I).
  • a first subgroup of compounds is constituted by the compounds for which X 1 , X 2 , X 3 and X 4 represent, independently of each other, a group C—R 1 ; and R 1 is chosen from a hydrogen atom, a halogen atom, more particularly a fluorine atom, and a group C 1 -C 6 -fluoroalkyl, more particularly a trifluoromethyl group.
  • a second subgroup of compounds is constituted by the compounds for which n is equal to 1 and Y represents an aryl, more particularly a phenyl, optionally substituted with one or more halogen atoms, more particularly fluorine atoms.
  • a third subgroup of compounds is constituted by the compounds for which W represents an oxygen atom.
  • a fourth subgroup of compounds is constituted by the compounds for which A represents the group
  • X 1 , X 2 , X 3 and X 4 represent, independently of each other, a group C—R 1 ; and R 1 is chosen from a hydrogen atom, a halogen atom, more particularly a fluorine atom, and a group C 1 -C 6 -fluoroalkyl, more particularly a trifluoromethyl group;
  • n 1;
  • Y represents an aryl, more particularly a phenyl, optionally substituted with one or more halogen atoms, more particularly fluorine atoms;
  • W represents an oxygen atom
  • A represents the group
  • leaving group means a group that can be readily cleaved from a molecule by breaking a heterolytic bond, with loss of an electron pair. This group may thus be readily replaced by another group during a substitution reaction, for example.
  • Such leaving groups are, for example, halogens or an activated hydroxyl group such as a methanesulfonate, benzenesulfonate, p-toluenesulfate, trifluoromethanesulfonate, acetate, etc. Examples of leaving groups and references for preparing them are given in “Advances in Organic Chemistry”, J. March, 5th Edition, Wiley Interscience, 2001.
  • protecting group means a group that can be momentarily incorporated into a chemical structure for the purpose of temporarily inactivating a part of the molecule during a reaction, and which may be readily removed in a subsequent synthetic step. Examples of protecting groups and references concerning their properties are given in T. W. Greene, P. G. M. Wutz, 3rd Edition, Wiley Interscience 1999.
  • the compounds of general formula (I) may be prepared according to the process illustrated by the general schemes 1 and 2 below:
  • compounds (I) may be obtained by reacting a compound of general formula (II), in which B represents an NH 2 group and X 1 , X 2 , X 3 , X 4 , n, Y and W are as defined in the general formula (I) above, with a compound of general formula (III), in which Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 3 are as defined in the general form above and D represents a leaving group, as defined above, for instance a bromine or iodine atom or a trifluoromethanesulfonate group,
  • the compounds of general formula (I) may also be obtained by reacting a compound of general formula (II), in which B represents a hydroxyl group and X 1 , X 2 , X 3 , X 4 , n, Y and W are as defined in the general formula (I) above, with a compound of general formula (III), in which Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are as defined in the general formula (I) above and D represents an NH 2 group, in the presence of a coupling agent such as diethyl cyanophosphonate or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, optionally in the presence of a base such as triethylamine, in a solvent, for instance dimethylformamide.
  • a coupling agent such as diethyl cyanophosphonate or N-(3-dimethylaminopropyl)-N
  • the compounds of general formula (I) may also be obtained by reacting a compound of general formula (II), in which B is a chlorine atom and X 1 , X 2 , X 3 , X 4 , n, Y and W are as defined in the general formula (I) above, with a compound of general formula (III), in which Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are as defined in the general formula (I) above and D represents an NH 2 group, in a solvent such as dichloroethane, toluene or tetrahydrofuran.
  • a compound of general formula (II) in which B is a chlorine atom and X 1 , X 2 , X 3 , X 4 , n, Y and W are as defined in the general formula (I) above, with a compound of general formula (III), in which Z 1 , Z 2 , Z 3 , Z 4 , Z 5
  • the compounds of general formula (II), for which B represents a group C 1 -C 6 -alkoxyl, may be converted into compounds of general formula (II), in which B represents a hydroxyl group, via the action of a base such as sodium hydroxide or potassium hydroxide in solution in a solvent such as ethanol.
  • the compounds of general formula (II), in which B represents a hydroxyl group may, thereafter, be converted into compounds of general formula (II), in which B represents a chlorine atom, via the action of a chlorinating agent such as thionyl chloride in a solvent such as dichloromethane.
  • a compound of general formula (V) in which X 1 , X 2 , X 3 , X 4 , n and Y are as defined in the general formula (I) above and PG represents a hydrogen atom, with a compound of general formula (IV), in which X represents a leaving group, as defined above, for instance a bromine or chlorine atom and R 2b is as defined in the general formula (I) above, for example according to a method similar to those described in J. Org. Chem. 1965, 30 (7), 2403 and Organometallics 2008, 27(8), 1936 or according to methods described in the literature or known to those skilled in the art.
  • the compounds of general formula (V), in which PG represents a hydrogen atom, may be obtained from compounds of general formula (V), in which PG represents a protecting group, for example an acetyl group, according to deprotection methods described in the literature or known to those skilled in the art.
  • the compounds of general formula (V) in which PG represents a protecting group, for example an acetyl group may be obtained by reacting a compound of general formula (II), in which B represents an NH 2 group and X 1 , X 2 , X 3 , X 4 , n and Y are as defined in the general formula (I) above, with a compound of general formula (VI), in which PG represents a protecting group, for example an acetyl group, and D represents a leaving group, as defined above, for instance a bromine atom or a trifluoromethanesulfonate group, for example according to a method similar to that described in J. Am. Chem. Soc.
  • the compounds of general formula (V) may also be obtained by reacting a compound of general formula (II), in which B represents a hydroxyl group and X 1 , X 2 , X 3 , X 4 , n and Y are as defined in the general formula (I) above, with a compound of general formula (VI), in which PG represents a protecting group, for example an acetyl group, and D represents an amino group, according to any coupling method known to those skilled in the art.
  • a subject of the invention is also the compounds of formulae (IIIa), (IIIb), (IIIc), (IIId), (IIIe) and (IIIf). These compounds are useful as synthetic intermediates for the preparation of the compounds of formula (I).
  • the compounds of formulae (IIIa), (IIIb), (IIIc), (IIId), (IIIe) and (IIIf) may be prepared, for example, according to the processes described in Examples 1, 8 and 14.
  • the compounds of general formula (I), for which one from among X 1 , X 2 , X 3 and X 4 corresponds to a carbon atom substituted with an alkyl group, may be obtained via a coupling reaction, catalysed with a metal such as palladium or iron, performed on the corresponding compounds of general formula (I), substituted with a halogen atom, such as a chlorine, in the presence, for example, of an alkylmagnesium halide or an alkylzinc halide, according to methods described in the literature (A. Furstner et al., J. Am. Chem. Soc. 2002, 124(46), 13856; G. Quéguiner et al., J. Org. Chem. 1998, 63(9), 2892), for example, or known to those skilled in the art.
  • the compounds of general formula (I), for which one from among X 1 , X 2 , X 3 and X 4 corresponds to a carbon atom substituted with a cyano, aryl or heteroaryl group, may be obtained via a coupling reaction, catalysed with a metal such as palladium, performed on the corresponding compounds of general formula (I), substituted, for example, with a bromine atom, in the presence of trimethylsilyl cyanide, an arylboronic acid or a heteroarylboronic acid, or via any other method described in the literature or known to those skilled in the art.
  • the compounds of general formula (I) substituted with a group C(O)NR 3 R 4 may be obtained from the corresponding compounds of general formula (I) substituted with a cyano group, according to methods described in the literature or known to those skilled in the art.
  • the compounds of general formula (I) substituted with a group —S(O)-alkyl or —S(O) 2 -alkyl may be obtained by oxidation of the corresponding compounds of general formula (I), substituted with a group thioalkyl, according to methods described in the literature or known to those skilled in the art.
  • the compounds of general formula (I), substituted with a group NR 3 R 4 , NR 5 COR 6 or NR 5 SO 2 R 7 may be obtained from the corresponding compounds of general formula (I), substituted with a nitro group, for example via reduction, followed by acylation or sulfonylation, according to methods described in the literature or known to those skilled in the art.
  • the compounds of general formula (I) in which W represents a sulfur atom may be obtained, for example, by reacting the corresponding compounds of general formula (I), in which W represents an oxygen atom, with a reagent such as Lawesson's reagent.
  • the compounds of general formula (I) for which R 2b corresponds to a hydroxyalkyl group may be obtained from compounds of general formula (I) for which R 2b corresponds, for example, to an acetoxyalkyl or pivaloyloxyalkyl group, according to chemical methods known to those skilled in the art, such as reaction with a base such as an aqueous sodium hydroxide solution, or reaction with an alkoxide, for example methoxide, of a salt such as lithium or sodium, in an alcoholic solvent such as methanol or ethanol.
  • the compounds of general formula (I) for which R 2b corresponds to a hydroxymethyl group may also be obtained from compounds of general formula (I) for which R 2b corresponds, for example, to an ethyl carboxylate group, by reaction with a reducing agent such as sodium borohydride, in a solvent such as tetrahydrofuran.
  • a reducing agent such as sodium borohydride
  • aqueous sodium hydroxide solution prepared from 1.15 g (28.92 mmol) of sodium hydroxide pellets in 50 mL of water, is added to a solution of 7.6 g (24.10 mmol) of ethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate (WO 2006/024776) in 241 mL of ethanol. The mixture is heated for two hours and then concentrated under reduced pressure. The resulting solid is taken up in 200 mL of water.
  • the solution is washed with twice 100 mL of ethyl ether, acidified by successive addition of small amounts of concentrated hydrochloric acid and then extracted with 200 mL of ethyl acetate.
  • the organic phase is finally washed twice with 100 mL of water, once with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. After drying at 50° C. under reduced pressure, 6.4 g of the expected product are obtained in the form of a solid, which is used without further purification in the rest of the synthesis.
  • the suspension is degassed for a few minutes, 0.01 mL (0.08 mmol) of trans-1,2-cyclohexanediamine is then added and the tube is closed.
  • the reaction mixture is stirred for 20 hours at 110° C.
  • the cooled suspension is filtered through a pad of silica, eluting with a mixture of dichloromethane and methanol.
  • the filtrate is concentrated under reduced pressure.
  • the resulting product is triturated in a mixture of 90 mL of isopropanol and 10 mL of isopropyl ether.
  • a solid is collected by filtration, and is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 27 mg of the expected product are thus obtained.
  • the suspension is degassed for a few minutes, 0.04 mL (0.31 mmol) of trans-1,2-cyclohexanediamine is then added and the tube is closed.
  • the reaction mixture is stirred for 20 hours at 110° C. After this time, the reaction mixture is diluted with 50 mL of water and 50 mL of ethyl acetate.
  • the aqueous phase is extracted with 2 ⁇ 50 mL of ethyl acetate.
  • the combined organic phases are washed with water (50 mL), dried over sodium sulfate and then concentrated under reduced pressure.
  • the resulting product is triturated in a boiling mixture of 30 mL of isopropyl ether and 10 mL of water. 0.63 g of the expected product is collected by filtration while hot, in the form of a white solid.
  • the reaction mixture is stirred for 15 hours at 110° C. After this time, the suspension, cooled to room temperature and is poured into 20 mL of water and 20 mL of ethyl acetate. The aqueous phase is extracted with 2 ⁇ 10 mL of ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The resulting product is triturated in a boiling mixture of 10 mL of dichloromethane and 30 mL of isopropyl ether and then filtered while hot. After drying, 0.31 g of the expected product is collected in the form of a beige-coloured solid.
  • the residue obtained is taken up in a mixture of 200 mL of saturated aqueous NaHCO 3 solution and 200 mL of ethyl acetate.
  • the phases are separated by settling and the aqueous phase is extracted with 200 mL of ethyl acetate.
  • the combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure. 0.46 g of the expected product is thus obtained.
  • the precipitate obtained is filtered off and rinsed successively with 2 mL of acetonitrile and 2 mL of isopropyl ether.
  • the solid obtained is dried under reduced pressure. 0.024 g of the expected product is thus obtained.
  • Compound 5 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, with 0.08 g (0.53 mmol) of 1-bromobutan-2-one in 4 mL of acetonitrile. 0.112 g of the expected product is thus obtained.
  • Compound 6 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, with 0.11 g (0.53 mmol) of 2-bromo-1-(thien-2-yl)ethanone in 4 mL of acetonitrile. 0.126 g of the expected product is thus obtained in the form of a white solid.
  • Compound 7 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, with 0.096 g (0.53 mmol) of 1-bromo-3,3-dimethylbutan-2-one in 4 mL of acetonitrile. 0.119 g of the expected product is thus obtained in the form of a white solid.
  • reaction mixture is then basified with aqueous sodium hydroxide solution (24%) and then extracted with three times 100 mL of dichloromethane.
  • the combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure.
  • the crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 110 mg of the expected product are thus obtained.
  • the suspension is degassed for a few minutes, and 0.01 mL (0.04 mmol) of trans-1,2-cyclohexanediamine is then added.
  • the tube is then sealed and heated in the microwave reactor at 150° C. for two 1-hour cycles. After this time, the suspension cooled to room temperature is poured into 20 mL of water and then extracted with 2 ⁇ 30 mL of dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure.
  • the crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 45 mg of the expected product are thus obtained.
  • the compound is prepared according to a process similar to that described in step 4.3, by reacting 0.2 g (0.53 mmol) of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 10.1, with 0.21 g (1.06 mmol) of ethyl 3-bromo-2-oxopropionate in 8 mL of acetonitrile. 70 mg of the expected product are thus obtained.
  • Compound 9 was prepared according to a process similar to that described in step 8.2, by reacting 0.465 g (0.98 mmol) of N-[2-(ethyloxycarbonyl)imidazo[1,2-a]pyrid-7-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 9.1, with 2.21 mL (2.21 mmol) of a molar solution of DIBAL-H in toluene, in 4 mL of dichloromethane. 80 mg of the expected product are obtained.
  • the tube is then sealed and heated in the microwave reactor at 170° C. for two 1-hour cycles, After this time, the suspension cooled to room temperature is poured into 50 mL of water and then extracted with 2 ⁇ 75 mL of dichlororomethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.425 g of the expected product is thus obtained in the form of a beige-coloured solid.
  • the crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.03 g of the expected product is thus obtained in the form of a beige-coloured solid.
  • Compound 11 was prepared according to a process similar to that described in step 10.2, by reacting 0.1 g (0.26 mmol) of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluoro-phenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 10.1, with 0.11 g (0.53 mmol) of 2-bromo-1-(thien-2-yl)ethanone in 4 mL of acetonitrile. 0.026 g of the expected product is thus obtained in the form of a beige-coloured solid.
  • Compound 12 was prepared according to a process similar to that described in step 10.2, by reacting 0.1 g (0.26 mmol) of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluoro-phenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 10.1, with 0.08 g (0.53 mmol) of 1-bromobutan-2-one in 4 mL of acetonitrile. 66 mg of the expected product are thus obtained.
  • Compound 13 was prepared according to a process similar to that described in step 10.2, by reacting 0.1 g (0.26 mmol) of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluoro-phenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 10.1, with 0.096 g (0.53 mmol) of 1-bromo-3,3-dimethylbutan-2-one in 4 mL of acetonitrile. 0.116 g of the expected product is thus obtained.
  • reaction mixture is stirred for 14 hours at 20° C. After this time, a solid is collected by filtration, and is triturated in 50 mL of diisopropyl ether. After filtering off and drying under reduced pressure, 1.5 g of the expected product are collected.
  • the suspension is degassed for a few minutes and 0.04 mL (0.33 mmol) of trans-1,2-cyclohexanediamine is then added.
  • the tube is then sealed and heated in the microwave reactor at 170° C. for 45 minutes. After this time, the suspension cooled to room temperature is poured into 30 mL of water and then extracted with 2 ⁇ 40 mL of dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure.
  • the crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.22 g of the expected product is thus obtained in the form of a white solid.
  • Compound 16 was prepared according to a process similar to that described in step 15.3, by reacting 0.12 g (0.28 mmol) of N-[2-aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared according to the protocol described in step 15.2, with 0.084 g (0.56 mmol) of 3-bromobutan-2-one in 5 mL of acetonitrile. 45 mg of the expected product are obtained.
  • the tube is then sealed and heated in the microwave reactor at 170° C. for 45 minutes. After this time, the suspension cooled to room temperature is poured into 30 mL of water and then extracted with 2 ⁇ 40 mL of dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.186 g of the expected product is thus obtained.
  • the compound is prepared according to a process similar to that described in step 15.3, by reacting 0.23 g (0.54 mmol) of N-[2-aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 17.2, with 0.21 g (1.07 mmol) of ethyl 3-bromo-2-oxopropionate in 4 mL of acetonitrile. 192 mg of the expected product are obtained.
  • reaction medium After stirring for 3 hours at room temperature, the reaction medium is poured slowly into a mixture (v/v) of water and concentrated sodium hydroxide, and is then extracted with 3 ⁇ 100 mL of dichloromethane. The combined organic phases are dried over magnesium sulfate and then concentrated under reduced pressure.
  • the crude reaction product obtained is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 30 mg of the expected product are thus obtained.
  • the compound is prepared according to a process similar to that described in step 15.3, by reacting 0.197 g (0.46 mmol) of N-[2-aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared according to the protocol described in step 15.2, with 0.179 g (0.92 mmol) of ethyl 3-bromo-2-oxopropionate in 5 mL of acetonitrile. 130 mg of the expected product are obtained.
  • Compound 18 was prepared according to a process similar to that described in step 17.4, by reacting 0.13 g (0.25 mmol) of N-[2-(ethyloxycarbonyl)imidazo[1,2-a]pyrid-7-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared according to the protocol described in step 18.1, with 0.32 mL of a molar solution of LiAlH 4 in 4 mL of tetrahydrofuran. 22 mg of the expected product are obtained.
  • Compound 19 was prepared according to a process similar to that described in step 10.2, by reacting 0.12 g (0.32 mmol) of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluoro-phenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 10.1, with 0.059 g (0.63 mmol) of 1-chloropropan-2-one in 4 mL of acetonitrile. 50 mg of the expected product are thus obtained.
  • the suspension is degassed for a few minutes, 0.053 g (0.46 mmol) of trans-1,2-cyclohexanediamine is added and the tube is closed.
  • the reaction mixture is stirred for 15 hours at 110° C. After this time, the suspension cooled to room temperature is poured into 50 mL of water and 50 mL of ethyl acetate.
  • the aqueous phase is extracted with 2 ⁇ 30 mL of ethyl acetate.
  • the combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure.
  • the resulting product is triturated in a boiling mixture of 5 mL of dichloromethane and 20 mL of isopropyl ether, and then filtered while hot.
  • the solid obtained is purified by chromatography on a column of silica, eluting with a mixture of n-heptane and ethyl acetate. After drying, 0.23 g of the expected product is collected in the form of a white solid.
  • reaction mixture is cooled to room temperature and the precipitate formed is filtered off, rinsed with a minimum amount of ethanol and then oven-dried under reduced pressure. 1.33 g of the expected product are obtained.
  • Compound 21 was prepared according to a process similar to that described in Example 20, by reacting 0.4 g (1.40 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 1.2, with 0.41 g (1.54 mmol) of ethyl 6-bromoimidazo[1,2-b]pyridazine-2-carboxylate, prepared according to the protocol described in step 21.1, in the presence of 80 mg (0.42 mmol) of copper iodide, 0.38 g (2.79 mmol) of potassium carbonate and 53 mg (0.46 mmol) of trans-1,2-cyclohexanediamine in 10 mL of dioxane. 20 mg of the expected product are thus obtained.
  • Compound 22 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, with 0.105 g (0.53 mmol) of ethyl 3-bromo-2-oxopropionate in 4 mL of acetonitrile. 0.05 g of the expected product is obtained in the form of a white solid.
  • Compound 24 was prepared according to a process similar to that described in Example 20, by reacting 0.5 g (1.75 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 1.2, with 0.35 g (1.75 mmol) of 6-bromo[1,2,4]triazolo[1,5-a]pyridine, in the presence of 99 mg (0.52 mmol) of copper iodide, 0.48 g (3.49 mmol) of potassium carbonate and 66 mg (0.58 mmol) of trans-1,2-cyclohexanediamine in 15 mL of dioxane. 393 mg of the expected product are thus obtained.
  • Table 1 illustrates the chemical structures and the physical properties of a number of compounds of general formula (I) according to the invention.
  • the compounds according to the invention underwent in vitro and in vivo pharmacological tests that demonstrated their value as therapeutically active substances. These compounds have antagonist or agonist activity towards the TRPV1 (or VR1) receptors.
  • DRG neurones naturally express the TRPV1 receptor.
  • the primary cultures of newborn rat DRGs are prepared using 1-day-old rats. Briefly, after dissection, the ganglions are trypsinized and the cells dissociated by mechanical trituration. The cells are resuspended in an Eagle basal culture medium containing 10% foetal calf serum, 25 mM KCl, 2 mM glutamine, 100 ⁇ g/ml gentamicin and 50 ng/ml of NGF, and then deposited on glass slides coated with laminin (0.25 ⁇ 10 6 cells per slide), which are then placed in Corning 12-well dishes. The cells are incubated at 37° C. in a humidified atmosphere containing 5% CO 2 and 95% air.
  • Cytosine ⁇ -D-arabinoside (1 ⁇ M) is added 48 hours after culturing, to prevent the growth of non-neuronal cells.
  • the slides are transferred into experimental chambers for the patch-clamp studies after 7-10 days of culturing.
  • the measuring chambers (volume 800 ⁇ l) containing the cell preparation are placed on the platform of an inverted microscope (Olympus IMT2) equipped with Hoffman optics (Modulation Contrast, New York) and observed at a magnification of 400 ⁇ .
  • the chambers are continuously gravity-influxed (2.5 ml/min) using a solution distributor accepting 8 inlets and whose sole outlet, consisting of a polyethylene tube (aperture 500 ⁇ m), is placed less than 3 mm from the cell under study.
  • the “whole cell” configuration of the patch-clamp technique was used.
  • the borosilicate-glass pipettes (resistance 5-10 MOhms) are brought to the cell by means of a 3D piezoelectric micromanipulator (Burleigh, PC1000).
  • the overall currents are recorded with an Axopatch 1D amplifier (Axon Instruments, Foster City, Calif.), connected to a PC running the Pclamp8 software (Axon Instrument).
  • the current plots are recorded on paper and simultaneously digitized (sampling frequency 15 to 25 Hz) and acquired on the hard drive of the PC.
  • the application of a 300 nM capsaicin solution induces on the DRG cells (voltage set at ⁇ 70 mV) an entering cationic current.
  • a minimum interval of 1 minute between two applications of capsaicin is observed.
  • the test compounds are applied alone at a given concentration (concentration of 10 nM or 1 nM) for a time of 4 to 5 minutes, during which several capsaicin+compound tests are performed (to obtain the maximum inhibition). The results are expressed as a percentage of inhibition of the control capsaicin response.
  • the percentages of inhibition of the capsaicin response (1 ⁇ M) are between 20% and 100% for the most active compounds of the invention tested at concentrations of from 0.1 to 100 nM. They are therefore effective antagonists of receptors of TRPV1 type. Table 2 gives a few examples of the percentage of inhibition obtained with the compounds of the invention.
  • the compounds of the invention may thus be used for the preparation of medicaments, especially for the preparation of a medicament for preventing or treating pathologies in which receptors of TRPV1 type are involved.
  • the compounds of the invention may be useful for preventing or treating pathologies in which receptors of TRPV1 type are involved.
  • a subject of the invention is medicaments comprising at least one compound of formula (I), or a pharmaceutically acceptable salt, or alternatively a hydrate or a solvate of the said compound.
  • medicaments find their therapeutic use especially in the prevention and/or treatment of pain and inflammation, chronic pain, neuropathic pain (trauma-related, diabetic, metabolic, infection-related or toxic pain, or pain induced by an anticancer or iatrogenic treatment), (osteo)arthritic pain, rheumatic pain, fibromyalgia, back pain, cancer-related pain, facial neuralgia, headaches, migraine, dental pain, burns, sunburn, animal bites or insect bites, post-herpetic neuralgia, muscular pain, trapped nerves (central and/or peripheral), spinal column and/or brain trauma, ischaemia (of the spinal column and/or the brain), neurodegeneration, haemorrhagic strokes (of the spinal column and/or of the brain) and post-stroke pain.
  • the compounds of the invention may also be used for preventing and/or treating metabolic disorders such as diabetes.
  • the compounds of the invention may be used for preventing and/or treating urological disorders such as hyperactivity of the bladder, vesical hyperreflexia, vesical instability, incontinence, urgent micturition, urinary incontinence, cystitis, nephritic colic, pelvic hypersensitivity and pelvic pain.
  • urological disorders such as hyperactivity of the bladder, vesical hyperreflexia, vesical instability, incontinence, urgent micturition, urinary incontinence, cystitis, nephritic colic, pelvic hypersensitivity and pelvic pain.
  • the compounds of the invention may be useful for preventing and/or treating gynaecological disorders, for instance vulvodynia and pain associated with salpingitis or with dysmenorrhoea.
  • These products may also be used for preventing and/or treating gastrointestinal disorders such as gastro-oesophageal reflux disorder, stomach ulcers, duodenal ulcers, functional dyspepsia, colitis, IBS, Crohn's disease, pancreatitis, oesophagitis and biliary colic.
  • gastrointestinal disorders such as gastro-oesophageal reflux disorder, stomach ulcers, duodenal ulcers, functional dyspepsia, colitis, IBS, Crohn's disease, pancreatitis, oesophagitis and biliary colic.
  • the products of the present invention may be useful in the prevention and/or treatment of respiratory disorders such as asthma, coughing, chronic obstructive pulmonary disease (COPD), bronchoconstriction and inflammatory disorders of the respiratory system.
  • respiratory disorders such as asthma, coughing, chronic obstructive pulmonary disease (COPD), bronchoconstriction and inflammatory disorders of the respiratory system.
  • COPD chronic obstructive pulmonary disease
  • These products may also be used for preventing and/or treating psoriasis, pruritus, dermal, ocular or mucous irritation, herpes and zona.
  • the compounds of the invention may also be used for treating depression.
  • the compounds of the invention may also be used for treating central nervous system diseases such as multiple sclerosis.
  • the compounds of the invention may also be used for treating cancers.
  • the present invention relates to pharmaceutical compositions comprising, as active principle, at least one compound according to the invention.
  • These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt, a hydrate or a solvate of the said compound and also at least one pharmaceutically acceptable excipient.
  • excipients are chosen, according to the pharmaceutical form and the desired mode of administration, from the usual excipients known to those skilled in the art.
  • compositions of the present invention may be administered via the oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal route. These compositions may be administered in a unit administration form, as a mixture with standard pharmaceutical excipients. They are intended to be administered to animals and human beings for the prophylaxis or treatment of the disorders or diseases mentioned above.
  • the appropriate unit forms of administration include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
  • oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions
  • sublingual, buccal, intratracheal intraocular and intranasal administration forms, forms for administration by inhalation
  • topical, transdermal, subcutaneous, intramuscular or intravenous administration forms rectal administration forms and implants.
  • the compounds according to the invention may be used in creams, gels, pomades or lotions.
  • a unit form of administration of a compound according to the invention in tablet form may comprise the following components:
  • the said unit forms are dosed to allow a daily administration of from 0.001 to 30 mg of active principle per kg of body weight, according to the galenical form.
  • the dosage that is appropriate for each patient is determined by the doctor according to the mode of administration, the weight and the response of the said patient.
  • the present invention also relates to a method for treating the pathologies indicated above, which comprises the administration to a patient of an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt, or hydrate or solvate thereof.

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US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
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US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10537580B2 (en) 2015-03-19 2020-01-21 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
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US9751857B2 (en) 2011-12-21 2017-09-05 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US9676747B2 (en) 2011-12-21 2017-06-13 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US10995064B2 (en) 2012-08-28 2021-05-04 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10941113B2 (en) 2013-02-28 2021-03-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10398677B2 (en) 2013-04-03 2019-09-03 Janssen Sciences Ireland Uc N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10160743B2 (en) 2013-05-17 2018-12-25 Janssen Sciences Ireland Uc Sulphamoylthiophenamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10457638B2 (en) 2013-05-17 2019-10-29 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10377709B2 (en) 2013-10-23 2019-08-13 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9873671B2 (en) 2014-01-16 2018-01-23 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10213420B2 (en) 2014-02-05 2019-02-26 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US10632112B2 (en) 2014-02-05 2020-04-28 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10537580B2 (en) 2015-03-19 2020-01-21 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US11129834B2 (en) 2016-04-15 2021-09-28 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases

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AU2009224534A1 (en) 2009-09-17
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HN2010001461A (es) 2013-06-10
KR20100105782A (ko) 2010-09-29
AU2009224534B2 (en) 2013-09-26
CA2712629A1 (fr) 2009-09-17
TN2010000295A1 (fr) 2011-11-11
CN101977910A (zh) 2011-02-16
FR2926556A1 (fr) 2009-07-24
PE20130230A1 (es) 2013-03-19
UA102088C2 (ru) 2013-06-10
FR2926556B1 (fr) 2010-02-19
NI201000125A (es) 2010-12-17
WO2009112679A1 (fr) 2009-09-17
ZA201005201B (en) 2011-09-28
PE20091403A1 (es) 2009-09-28
NZ587014A (en) 2012-06-29
CL2009000120A1 (es) 2010-03-05
IL207080A0 (en) 2010-12-30
MX2010007976A (es) 2010-08-04
US20110009444A1 (en) 2011-01-13
EP2235016B1 (fr) 2013-09-18
UY31608A1 (es) 2009-08-31
EA201070873A1 (ru) 2010-12-30
TW200936584A (en) 2009-09-01
CO6280508A2 (es) 2011-05-20
CA2712629C (fr) 2016-08-02
EP2235016A1 (fr) 2010-10-06
CR11547A (es) 2010-09-13
CN101977910B (zh) 2013-08-07
MA32090B1 (fr) 2011-02-01
ECSP10010356A (es) 2010-08-31
AR070208A1 (es) 2010-03-25
JP5490723B2 (ja) 2014-05-14

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